[HTML][HTML] Identification of ADAR1 adenosine deaminase dependency in a subset of cancer cells

HS Gannon, T Zou, MK Kiessling, GF Gao, D Cai… - Nature …, 2018 - nature.com
HS Gannon, T Zou, MK Kiessling, GF Gao, D Cai, PS Choi, AP Ivan, I Buchumenski
Nature communications, 2018nature.com
Systematic exploration of cancer cell vulnerabilities can inform the development of novel
cancer therapeutics. Here, through analysis of genome-scale loss-of-function datasets, we
identify adenosine deaminase acting on RNA (ADAR or ADAR1) as an essential gene for
the survival of a subset of cancer cell lines. ADAR1-dependent cell lines display increased
expression of interferon-stimulated genes. Activation of type I interferon signaling in the
context of ADAR1 deficiency can induce cell lethality in non-ADAR1-dependent cell lines …
Abstract
Systematic exploration of cancer cell vulnerabilities can inform the development of novel cancer therapeutics. Here, through analysis of genome-scale loss-of-function datasets, we identify adenosine deaminase acting on RNA (ADAR or ADAR1) as an essential gene for the survival of a subset of cancer cell lines. ADAR1-dependent cell lines display increased expression of interferon-stimulated genes. Activation of type I interferon signaling in the context of ADAR1 deficiency can induce cell lethality in non-ADAR1-dependent cell lines. ADAR deletion causes activation of the double-stranded RNA sensor, protein kinase R (PKR). Disruption of PKR signaling, through inactivation of PKR or overexpression of either a wildtype or catalytically inactive mutant version of the p150 isoform of ADAR1, partially rescues cell lethality after ADAR1 loss, suggesting that both catalytic and non-enzymatic functions of ADAR1 may contribute to preventing PKR-mediated cell lethality. Together, these data nominate ADAR1 as a potential therapeutic target in a subset of cancers.
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